1. Field of the Invention
The present invention relates to a novel processes for the preparation of carbapenem intermediates that are useful to produce Ertapenem, Meropenem and Doripenem and further provides an effective process for recovering and purifying ertapenem compounds.
2. The Prior Arts
The carebapenem are among the most broadly effective antibiotics making them useful in the treatment of a wide range of bacterial infections including against both Gram positive and negative, aerobic and anaerobic bacteria. Since carbapenems were first isolated from fermentation media in 1974, several problems with the development of antibiotic resistance in bacteria and novel untreatable bacteria have been appeared. The continuing emergence of bacteria exhibiting resistance to existing therapeutic agents has made development of new carbapenem an important part of our strategy in addressing this problem.
Ertapenem of carbapenem antibiotics is commercially available as Invanz® from Merck, and has chemical name [4R,5S,6S]-3-[[(3S,5S)-5-[[(3-carboxyphenyl)amino]carbonyl]-3-pyrrolidinyl]-thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic-acid which can be used as an intravenous infusion or intramuscular injection. 1β-methylcarbapenem antibiotic is Ertapenem of formula (II) in the present invention, and used as antibiotic agent in the treatment of moderate to severe complicated foot infection due to indicated pathogens in diabetic patients without osteomyelitis, 1β-methylcarbapenem antibiotic is also useful in the treatment of pneumonia, urinary tract infections, intra-abdominal, gynecological, skin, and soft tissue infections, meningitis, septicemia and febrile Neutrogena.
In view of the importance of 1β-methylcarbapenem antibiotic, several synthetic procedures to prepare the compound have been reported. U.S. Pat. No. 5,478,820 and U.S. Pat. No. 5,856,321 claim various processes for preparing Ertapenem and its sodium salt. Example 12 of U.S. Pat. No. 5,487,820 discloses a process in which the Ertapenem was isolated by using column purification as well as freeze-drying technique. Example 1 of U.S. Pat. No. 6,180,783 also provides an improved process for carbapenem synthesis by using hydrophobic resin purification and then nanofiltration to obtain the product in the stabilized form. Therefore, this is an expensive, labor intensive technique, and the long-time process may cause instability of the product.
U.S. Pat. No. 6,504,027 provides a process for preparing Ertapenem in crystalline form and the document also reported about development of a procedure for the production of the ertapenem (J. Org. Chem. 2005, 70, 7479-7487). However, the process for deprotecting the mono-protected Ertapenem is more complicated and more unstable intermediates therein and the reaction conditions is more stringent and higher material costs. In addition, there general problems with preparation of Ertapenem compounds such as occurrence of undesired by-products, complexity of synthesis, low yields, and subsequently high cost.
In the preparation of Ertapenem, consideration of above characteristics, the loss of the ertapenem in the reaction solution was about 15 to 20%. Therefore, it is necessary to develop a method for recovering and purifying of ertapenem (Ertapenem) form the reaction solution with economic and efficient steps. J. Chromatogr A. 1079, 80-91 (2005) refers to several operating procedures, such as high-pressure column chromatography (HPLC), −70° C. ultra-low temperature preservation and long-time distillation. Since these prior arts involve number of operations which are expensive, labor intensive techniques and subsequently high cost, it is not easy to carry out a great deal of recovery after using the above operating procedures.
In addition, the recovery and the purification of Ertapenem reaction solution is difficult since several reasons, such as the concentration is too low to crystallize (about 2˜8 mg/ml), high levels of impurities (about 50˜60%), the complex composition of the reaction solution, and the product is damaged with time.